1. Anatomy of an Amyloidogenic Intermediate
Roger S. Armen, Darwin O.V. Alonso, Valerie Daggett 
Structure 
Volume 12, Issue 10, Pages (October 2004)
DOI: /j.str

2. Figure 1 Diagram of the Amyloidogenic Pathway for TTR
Patterned after figures of Kelly and coworkers, for example (see Kelly et al. [1997]).
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3. Figure 2
Topology Map, Crystal Structure of TTR, and Changes to the Structure during MD
(A) Topology map and crystal structure of TTR. Topology map was drawn using the TOPS software (Westhead et al., 1999).
(B) Crystal structure of TTR (Hamilton et al., 1993).
(C) Cα rms deviation from the starting structure as a function of simulation time for the monomer simulations at 310 K.
(D) Cα rms deviation from the starting structure as a function of residue number for the simulations in (C). UCSF MidasPlus (Ferrin et al., 1988) was used to make Figures 2, 3, and 5–11.
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4. Figure 3 Structure of the DAGH-Sheet of TTR (A) Crystal structure.
(B) α-sheet structure in the L4 intermediate. Above each hydrogen bond is the percentage of simulation time the hydrogen bond is intact over the time interval when the intermediate was populated (Table 1).
(C) Structure of the 25 ns DAGH-sheet from the 310 K simulation at low pH. Above each hydrogen bond is the percentage of simulation time the hydrogen bond is intact from 20 to 25 ns.
(D) Structure of the 50 ns DAG-sheet from 310 K simulation at medium pH. Above each hydrogen bond is the percentage of simulation time the hydrogen bond is intact from 40 to 50 ns.
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5. Figure 4
Pairwise Cα Rmsd Matrix Comparing All Nine Medium- and Low-pH Unfolding Trajectories at 498 K
The x and y coordinates indicate the time points of the structures being compared, ranging from 0–3 ns in each box, with color-coded rmsds. The magnitude of the Cα rmsd is give in the color scale to the right of the plot (0–2 Å, black; 2–4 Å, red; 4–6 Å, purple; 6–8 Å, blue; 8–10 Å, green; 10–12 Å, cyan; and 12–25 Å white). On-diagonal clusters indicative of a conformational ensemble are represented by a thickening of the diagonal. The presence of off-diagonal clusters suggests that the corresponding on-diagonal clusters belong to a common unfolding intermediate.
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6. Figure 5 Structures of TTR Thermal Unfolding Intermediates at 498 K
The secondary structure is only shown in the ribbon diagram when it is persistent in the intermediate. The backbone conformation is shown for persistent elements of secondary structure in the DAGH-sheet.
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7. Figure 6 Side Chain Packing for the α-Sheet and the β-Sheet
(A) Hydrophilic face of the AGH-sheet.
(B) Hydrophobic face of the AGH-sheet. The bottom panel was made using MolScript (Kraulis, 1991).
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8. Figure 7 Comparison of Simulation Structures to Hydrogen Exchange Data
(A) Experimental hydrogen exchange profile at pH 5.75 mapped onto the crystal structure, as in Liu et al. (Liu et al., 2000a, 2000b). Amides that undergo complete exchange within 2 hr are shown in green, amides that exchange in 72 hr are shown in yellow, and amides that are protected for more than 500 hr are shown in blue.
(B) Experimental hydrogen exchange profile at pH 4.5 mapped onto the crystal structure as in Liu et al. (2000a, 2000b). The backbone amides of 14 residues in the DAGH-sheet that remain protected are shown in blue. The backbone amides of the 13 residues that show elevated exchange rates at pH 4.5 are shown in magenta.
(C) Predicted hydrogen exchange profile from the L4 intermediate mapped onto the 0.6 ns structure. Backbone amides predicted to be protected are shown in blue, and amides predicted to exchange with solvent are shown in magenta.
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9. Figure 8
Representative Structures of Unfolding Intermediates at Different pHs and Temperatures
The secondary structure is depicted with a ribbon when it is highly persistent in the intermediate. Tyr, Phe, and Trp are shown and colored cyan. Amyloid-specific antibody binding epitopes, residues 39–44 and 56–61, are shown in red.
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10. Figure 9
Structures from the PDB with Experimentally Defined Bifurcation of α-Sheet Hydrogen Bonding
Structures from the PDB with experimentally defined bifurcated hydrogen bond networks in β-bulges. Different experimentally determined ([A], NMR; [B and C], crystal structures) but structurally related structures are displayed to illustrate bifurcated hydrogen bonding as seen in α-sheets. Main chain dihedral angles are provided for selected residues along with their conformation.
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11. Figure 10
Conformation of Residues 105–115 in the Crystal Structure and in a Snapshot from the L4 Intermediate Ensemble
Below each structure is a plot of the corresponding calculated chemical shifts for these residues compared with the experimental values.
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12. Figure 11 α-Sheet Amyloidogenic Intermediate Model
(A) Structures of representative α-sheet unfolding intermediates.
(B) Possible topologies for the amyloidogenic intermediate based on the results of our simulations.
(C and D) Schematic α-sheet intermediate model for self-assembly into amyloid. A main chain model for an all α-sheet AGH-sheet is shown with the partial charges on the interface in red for negative and blue for positive charges.
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